tbuckley/cabot-search huggingface dataset:
Abstract 2960: KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs
Authors: Andres Blanco
Journal: Cancer Research (2022)

Abstract Acute myeloid leukemia (AML) is a poor-prognosis hematological malignancy that is characterized by differentiation blockade and uncontrolled proliferation. Epigenetic programs influence AML cell fate decisions, and their mis-regulation can promote differentiation arrest. Itis therefore of paramount importance to identify the regulators of AML cell differentiation and understand the mechanisms by which they repress myeloid transcriptional programs. Here, we performed a cell-fate selection CRISPR screen for chromatin factors whose inhibition promotes AML cell differentiation. We found that the histone acetyltransferase KAT6A is a critical driver of the differentiation block, and that both genetic and chemical inhibition of KAT6A markedly de-repressed latent myeloid maturation programs, most commonly in MLL-rearranged AML. Inhibition of KAT6A catalytic activity reduced self-renewal, induced cell cycle arrest, and extinguished long-term proliferative capacity of AML cells. Through ChIP-seq, RNA-seq, and extensive analysis of clinical datasets, we found that KAT6A is the likely initiator of a newly-described "writer-reader" module that drives oncogenic gene expression in AML. In this model,KAT6A catalyzes promoter H3K9 acetylation, which is bound by the H3K9ac reader ENL, leading to Super elongation complex (SEC) recruitment and release of paused RNA PolII at oncogenic loci such as MYC. KAT6A is elevated in human AMLs compared to matched normal tissue, and its downregulation correlates with monocytic differentiation transcriptional programs in clinical AML datasets. These findings suggest the potential of targeting both KAT6A and ENL to disrupt this writer-reader module and ablate downstream MYC transcriptional programs inMLL-rearranged AML. Citation Format: Andres Blanco. KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2960.
Abstract 5966: Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting
Authors: Kasimu Umar Adoke, Sanusi Mohammed Haruna
Journal: Cancer Research (2022)

Abstract Since the incidence of Malignant melanoma (MM) is rising, we propose high quality patient samples bio-bank for proper understanding of the disease and with time analyze on a large scale proteogenomics. There is increased need to support research and help improved patient care and outcome. Bio-banking in MM will provide high quality and well define tissue and bio-fluid specimens. Materials and Methods: Large scale sample collection were done for 22 patients with histological diagnosis of MM. The patients consent and hospital ethical approval was sorted for the study, with patients' fresh frozen tissue and blood samples collected, fractionated and stored in an automated bio-bank. Five patients however did not consent for bio-banking of their samples. Results: Patients that consented to sample collection had proteogenomic studies and other studies were done on their specimens with possibilities of new treatments for the patients and precision oncology for these patients tailored on their unique genomic landscape. Conclusion: Bio -banking on a large scale is possible and helpful in MM patient especially in our environment where most patients are lost to follow up and have high degree of resistance and mortality during chemo radiation treatment. Citation Format: Kasimu Umar Adoke, Sanusi Mohammed Haruna. Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5966.
Reply
Authors: Zhewen Ren, Pomme I. H. G. Simons, Anke Wesselius, Coen D. A. Stehouwer, Martijn C. G. J. Brouwers
Journal: Hepatology (2022)

There was a biological and a methodological rationale for repeating our Mendelian randomization (MR) analyses after exclusion of very low density lipoprotein (VLDL) secretion genes. First, nonalcoholic fatty liver disease (NAFLD) is a complex phenotype. The first stage, simple steatosis, is caused by a disbalance between the input of lipids (i.e., influx of free fatty acids and de novo lipogenesis) and the output of lipids (i.e., fatty acid oxidation and VLDL secretion) from the liver. Stable isotope studies have shown that these four pathways are not equally represented in the average patient with NAFLD. Particularly, rates of free fatty acid flux and de novo lipogenesis are increased.[1] Furthermore, stable isotope studies have also shown that VLDL secretion rate is increased, rather than impaired, in NAFLD.[2] By excluding VLDL secretion genes, that is, genes that cause NAFLD by impairment of VLDL secretion, we aimed to align our instrumental variables to the average patient with NAFLD. It should be noted that we do not deny that genes that impair VLDL secretion cause NAFLD. Second, as Zhao and Xun correctly state, the results of MR studies are only valid when horizontal pleiotropy has been excluded. As indeed explained previously, genes that cause NAFLD by impairment of VLDL secretion are an example of horizontal pleiotropy (confounding), because they inherently cause low serum lipid levels.[3] This conclusion is also supported by our MR Egger analyses showing that the statistically significant intercept, indicative of horizontal pleiotropy, was no longer observed after exclusion of these genes.[4] Of note, it is likely that there are genes in the remaining dataset that are associated with increased VLDL secretion as a consequence of NAFLD. This is an example of vertical pleiotropy (mediation) that indeed does not violate the MR assumptions and, in fact, appears to be one of the major pathways linking NAFLD to coronary artery disease.[3,5] In conclusion, we believe that by excluding genes that cause NAFLD by impairment of VLDL secretion, our MR results are more valid and clinically relevant. For Zhao and Xun's final remark regarding the proxies of NAFLD used in our study, we would like to refer to the strengths and limitations paragraph in the original manuscript. CONFLICT OF INTEREST Nothing to report.
Abstract 1642: Evaluating <i>in vivo</i> efficacy of anti-VSIG4 antibodies in humanized B-hVSIG4 mice
Authors: Ruili Lyu, Chengzhang Shang, Leila Kokabee, Yanhui Nie, Yi Yang
Journal: Cancer Research (2022)

Abstract V-set and immunoglobulin domain containing 4 (VSIG4) protein is an immune checkpoint molecule that is related to the B7 family of immune regulatory proteins. B7 family members have been implicated in both positive and negative regulation of T cell activation, particularly VSIG4 is a known negative regulator of T cell proliferation and IL-2 production. Pathological consequences of VSIG4 expression are associated with inflammatory disorders, lung cancer development, high-grade glioma, and multiple myeloma, suggesting VSIG4 is a potential target for drug development. Therefore, Biocytogen developed humanized VSIG4 mice (B-hVSIG4 mice) by replacing the murine Vsig4 gene with the human VSIG4 gene through homologous recombination. Flow cytometry analysis showed human VSIG4 was detectable in peritoneal exudate macrophages (PEMs) in homozygous B-hVSIG4 mice compared to wild type mice. Additionally, percentages of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hVSIG4 mice were similar to those in wild type mice, demonstrating that introduction of human VSIG4 in place of its mouse counterpart does not change the overall development, differentiation or distribution of these cell types. For in vivo efficacy evaluation of an anti-human VSIG4 antibody (Ab-A, synthesized in house) using B-hVSIG4 mice, mouse colon adenocarcinoma MC38 cells were subcutaneously implanted into homozygous B-hVSIG4 mice (female, 7-week-old, n=5). Mice were grouped and treated when the tumor volume reached approximately 100 mm3. Results showed that an anti-hVSIG4 antibody was efficient at inhibiting tumor growth in B-hVSIG4 mice. In conclusion, B-hVSIG4 mice are as a promising model for preclinical in vivo studies to assess pharmacodynamic of anti-hVSIG4 antibodies. Keywords: VSIG4, humanized mice, immune checkpoint molecule Citation Format: Ruili Lyu, Chengzhang Shang, Leila Kokabee, Yanhui Nie, Yi Yang. Evaluating in vivo efficacy of anti-VSIG4 antibodies in humanized B-hVSIG4 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1642.
Abstract 913: Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers
Authors: Inigo Landa, Jingzhu Hao, Bin Xu, Joseph Giacalone, Zach Herbert, Maria A. Blasco, Jeffrey A. Knauf, Ronald Ghossein, James A. Fagin
Journal: Cancer Research (2022)

Abstract Hotspot mutations in the proximal promoter of the telomerase reverse transcriptase (TERT) gene are the first cross-cancer alterations lying in a gene regulatory region. TERT promoter mutations (TPMs) are enriched in advanced thyroid tumors and constitute markers of disease severity. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bone fide oncoprotein. To study TERT deregulation and its downstream consequences in a biologically accurate model, we generated a Tert-mutant promoter mouse model via CRISPR/Cas9 editing of the equivalent murine locus and crossed these animals with thyroid-specific BrafV600E-mutant mice. BrafV600E animals develop highly penetrant papillary thyroid tumors (PTC) by week 5, but do not progress. In contrast, BrafV600E+TertMUT animals showed an increased incidence of poorly differentiated thyroid cancers (PDTC) by 20 weeks (30% vs. 0% in BrafV600E; chi-squared P= 0.03), mimicking those exhibited by an alternative transgenic model of Tert overexpression (BrafV600E+K5-Tert; 36% PDTCs). Mouse Tert promoter mutation increased Tert transcription in vitro and in vivo, as reported in patients’ tumors carrying TPMs. Braf+Tert animals partially responded to MAPK pathway inhibition (dabrafenib plus trametinib), showing that MAPK signaling remains relevant in these specimens. Interestingly, RNA sequencing of Tert-reactivated murine thyroid tumors showed unique transcriptomic profiles (compared to BrafV600E alone), suggesting that downstream effects, other than the canonical Tert-mediated telomere maintenance, operate in cancers harboring TPMs. These cancer models of telomerase reactivation provide excellent pre-clinical settings to understand the regulatory mechanisms and biological underpinnings of TPM-induced progression of thyroid and other tumors, and to explore novel therapeutic strategies. Citation Format: Inigo Landa, Jingzhu Hao, Bin Xu, Joseph Giacalone, Zach Herbert, Maria A. Blasco, Jeffrey A. Knauf, Ronald Ghossein, James A. Fagin. Tert mutant promoter mouse model induces cancer progression in BrafV600E-driven thyroid tumors: A novel tool to understand the biology of telomerase-reactivated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 913.
Abstract LB052: Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis
Authors: Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando
Journal: Cancer Research (2022)

Abstract Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Aβ decreases brain metastatic burden. Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer’s disease - two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. Citation Format: Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB052.
Abstract 6312: The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies
Authors: Asli Kucukosmanoglu, Silvia Scoarta, Thomas Wijnands, George Kanev, Bart Westerman, Bert Kiewit, David Noske, Tom Wurdinger
Journal: Cancer Research (2022)

Abstract The current gold-standard of estimating adverse events of a drug are clinical trials. However, these trials fail to represent real-life practice where patients have additional diseases (comorbidities) and commonly use numerous drugs when entering the clinic. Therefore, there is a rise of interest in combinational therapies, also because effective combinations are expected to prevent therapy resistance. At this moment it is not feasible to predict the adverse events of new combination therapies due to lack of available information both from a dimensionality (i.e., number of adverse events recorded per patient) as well as from a patient-number perspective. When available, this information allows to choose combinational therapies with acceptable adverse events. In this study we developed a preliminary method to predict adverse events of drug combinations in order to select combinations with a mild adverse event profile. We used the FAERS, an FDA post-marketing adverse events registry as data source containing 15 million adverse-event records. First, we developed a method to visualize the adverse events profiles of monotherapy and combination therapy using dimension reduction to accurately represent the relation between adverse events over many patients. These adverse-event profiles are then fed to a convolutional neural network (CNN) to generate an explainable prediction-model for adverse events occurring in combination therapies. The CNN trained on monotherapy is able to learn from the data and recognize adverse event patterns. The learned pattern information, as stored in the so-called latent space, can be converted back onto the original adverse event profiles. This showed a high similarity to the original data, also for unseen combination therapy effects. Furthermore, a t-SNE analysis on the latent space of the CNN is able to separate additive and synergistic adverse event patterns in combination therapy. Our CNN model can successfully learn complex adverse-event patterns for single drugs and their combinations, which are all encoded in the latent space. The developed method is therefore applicable to determine the combinatorial effects of highly complex adverse event profiles. Citation Format: Asli Kucukosmanoglu, Silvia Scoarta, Thomas Wijnands, George Kanev, Bart Westerman, Bert Kiewit, David Noske, Tom Wurdinger. The adverse events atlas, towards a strategy to predict synergistic adverse events of combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6312.
Abstract 2327: Dysregulated TCA cycle is associated with endocrine therapy resistance in ER+ breast cancer cells
Authors: Surojeet Sengupta, Karla Andrade de Oliviera, Lu Jin, Robert Clarke
Journal: Cancer Research (2022)

Abstract Estrogen receptor positive (ER+) breast cancer is the most common breast cancer subtype. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), along with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are the current mainstays of treatment. Despite being initially effective, the majority of advanced ER+ breast cancers become resistant to the endocrine therapies. Therefore, it is important to understand the underlying molecular mechanisms that enable or promote resistance to endocrine therapies. Rapidly proliferating cells have a high energy demand and consequently consume greater quantities of glucose to fulfill their energy and anabolic demands to support cell growth. Using endocrine therapy sensitive and resistant breast cancer cell models we investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose and measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. The TCA cycle was noticeably impaired in LCC9 cells as the C-13 labelled citrate (m+4 and m+6) isotopomer was absent in these cells. In addition, C-13 labelled fumarate was very low in LCC9 cells with a concurrent increase in the succinate:fumarate ratio. These observations show that in LCC9 cells the TCA cycle is dysregulated at the succinate to fumarate conversion step, which is catalyzed by the succinate dehydrogenase (SDH) enzyme. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Further investigation revealed that SDHAF2 was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, SDH inhibition by dimethyl-malonate re-sensitized LCC9 cells to both Fulvestrant and 4-hydroxytamoxifen. Clinically, lower expression levels of SDHAF2 correlates with poor relapse free survival in ER+ breast cancer patients. In summary, our study suggests that accumulation of succinate driven by deficient SDH activity is functionally associated with endocrine therapy resistance in ER+ breast cancer cells. Citation Format: Surojeet Sengupta, Karla Andrade de Oliviera, Lu Jin, Robert Clarke. Dysregulated TCA cycle is associated with endocrine therapy resistance in ER+ breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2327.
Abstract 5008: The potential role of hsa-miR-3157-3p in prostate cancer pathogenesis
Authors: Akhil Wali, Hari Koul
Journal: Cancer Research (2022)

Abstract Prostate cancer remains a major area of concern as it is the second leading cause of cancer mortalities amongst American men. Our study aimed to find the role of differentially expressed microRNAs that play a role in prostate cancer etiopathology. With the use of the National Center for Biotechnology Information (NCBI), we narrowed down a desired dataset (GSE138740). While analyzing the dataset, we found the expression pattern of hsa-miR-3157-3p (adjusted p-value 0.04797) to be significantly upregulated in low grade tumor samples (Gleason Score 6 and n=88) compared to high grade tumor samples (Gleason Score 8,9 and n=13). Furthermore, the role of hsa-miR-3157-3p in prostate cancer remains a novel finding. We have identified target genes such as E2F3, UBE2M, ABCF1, PKN3 and VANGL1 using the RNA Central website portal. Further studies are underway to elucidate the expression pattern of this miRNA and it’s target genes that would correlate with the disease progression observed among tumor samples in The Cancer Genome Atlas (TCGA) database. The Ingenuity Pathway Analysis (IPA) software generated report will be presented at the meeting to describe gene networks and pathways implicated in Prostate Cancer. Overall, these studies are designed to further validate whether this miRNA and its target genes can serve as potential biomarkers to predict the onset and progression from low to high grade prostate cancer. Citation Format: Akhil Wali, Hari Koul. The potential role of hsa-miR-3157-3p in prostate cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5008.